Jani, Prachi

Abstract Background: Multiple myeloma (MM) is characterized by the invasion of malignant plasma cells into the bone marrow. While first line treatment options result in significant clinical benefit to patients, spatiotemporal clonal evolution results in disease relapse and mortality. Advances in genomics have armed clinicians with unprecedented insight into the molecular architecture of MM cells, however, the clinical benefit derived by genomics-guided intervention has been limited. We present a novel computational biology modelling (CBM) tool, which takes into account the combined effect of individual mutations, gene copy number abnormalities and large scale chromosomal changes in order to predict the salient molecular pathways utilized by the MM cell for survival. By reverse-engineering MM cell architecture in silico, the CBM tool is able to predict drug response and resistance mechanisms. Thus, our aim was to determine the accuracy of the CBM tool in predicting treatment response of relapsed/refractory MM patients for future management of their disease, in a more individualized manner. Methods: Cytogenetics and somatic mutations (by targeted NGS) for 15 MM patients were input into the CBM model to predict responses to different therapeutic combinations. All patients were relapsed to prior treatment. CBM uses PubMed and other online resources to generate patient-specific protein network maps of activated and inactivated disease pathways. We simulated the specific combinations of the drugs per patient and measured the quantitative drug effect on a composite MM disease inhibition score (i.e., cell proliferation, viability, apoptosis and paraproteins). The actual clinical outcome of the treatments was compared with predicted outcomes. Results: Fifteen patients were analysed using CBM for prediction of treatment response after NGS was performed. 13/15 were clinically evaluable, of which 1 was a responder and 12 were non-responder. 6/13 patients were treated on clinical trial and 7/13 were on drug combinations per physician decision. CBM correctly predicted 1 responder and 11 non-responder with a PPV of 50%, NPV 100%, specificity 91.67%, sensitivity 100%. The accuracy of CBM prediction was 92.30%. CBM also predicted the response of prior drug therapies for its non-response at relapse. For prior drug treatment options, 14 patients were evaluable. All the 14 patients were clinically non-responders and CBM correctly predicted for 13 patients with NPV 100%, Specificity 92.85% and overall accuracy of 92.85%. The majority of patients did not respond to therapies recommended at relapse. As an example, the operative molecular pathways from 2 patients who did not respond to combination treatment, either pre-NGS or post-NGS profiling, are shown in Fig. 1 and Table 1. CBM identified amplification (AMP) of chromosome (chr) 1 (WNT3A, IL6R, CKS1B, MCL1, PIK3C2B, USF1), chr 3 (HES1, PIK3CA, CTNNB1, WNT7A, FANCD2), chr 5 (IL6ST, IRF1, GLRX, SKP2), chr 7 (CDK5, EZH2, IL6, CAV1, ABCB1), chr 9 (NOTCH1, HSPA5, FANCC, FANCG), chr 15 (DLL4, FANCI, ALDH1A2), chr 19 (ERCC1, ERCC2, USF2); deletion(DEL) of chr 13 (CUL4A) , chr 16 (AXIN1, CDH1) and TP53 mutation in different combinations, which confer resistance to therapies at relapse. Conclusions: The CBM technology represents a potential means to identify therapeutic options for MM patients based on the patients individual tumor-genome profile and which can also be deployed for uncovering drug resistance mechanisms. This tool may aid clinicians in decision making for recommending the most appropriate therapy based on standard of care agents or clinical trials; thus improving patient outcomes and reducing unnecessary costs or drug-related toxicities. Disclosures Singh: Cellworks Research India Private Limited: Employment. Sauban:Cellworks Research India Private Limited: Employment. Husain:Cellworks Research India Private Limited: Employment. Kumar:Cellworks Research India Private Limited: Employment. Kumari:Cellworks Research India Private Limited: Employment. Tyagi:Cellworks Research India Private Limited: Employment. Abbasi:Cell Works Group Inc.: Employment. Vali:Cell Works Group Inc.: Employment. Ailawadhi:Pharmacyclics: Research Funding; Takeda: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Janssen: Consultancy.

Abstract Background: Therapeutic advancements have led to significant improvement in outcomes for MM patients. Revised diagnostic criteria from International Myeloma Working Group focus on initiating treatment before the onset of end-organ damage. Thus, timeliness of initial therapy can significantly improve patient morbidity and outcomes. Such an analysis has not been reported for MM. Methods: We analyzed patients diagnosed with MM between 2004-2015 from the National Cancer Database (NCDB). Patients who received systemic treatment any time within the first year of diagnosis were included; those treated later than one year were considered possibly initially diagnosed with smoldering myeloma and hence, excluded. Time to initial treatment was divided into centiles with the 4 centiles analyzed being 0-7 days, 8-18 days, 19-37 days and >37 days. We performed univariate and multivariate analyses to compare sociodemographic and clinical factors influencing patient distribution across these timeliness categories and trends over time. Results: A total of 53,665 patients were included with 15,282 in 0-7 days, 12,462 in 8-18 days, 12,723 in 19-37 days and 13,198 in the >37 days treatment categories. Distribution across these centiles over time is shown in Figure. Univariate analyses showed a significant difference in distribution across the timeliness categories by year of diagnosis, patient age, gender, race/ethnicity, education level, insurance type, comorbidity score, treatment facility type, geographical location and distance to treating facility (all p<0.001) but no effect of income level. Multivariate analysis showed that there was a significantly higher likelihood of being in 4th centile (>37 days to treatment) for women (p<0.001), African Americans (p<0.001) or Hispanics (p=0.03; reference: Whites) or diagnosed in more recent years (p<0.001). Patients were less likely to be in the 4th centile if they were ≥80 years (HR 0.89, 95% CI 0.81-0.98, p=0.02), had >0 Charlson comorbidity score (p<0.001), were uninsured (p=0.02) or had Medicaid (p=0.03) as compared to having private insurance, were in non-community treatment facilities or geographical location other than Northeast (p<0.001). Patient education, income level or distance from treating facility was no longer significant. Conclusions: Several factors were found to affect timeliness of treatment in MM. We noted relatively faster time to initial treatment in elderly, uninsured or those who were treated in academic/comprehensive cancer programs but a delay in treatment for women and racial/ethnic minorities among other factors. These factors need to be addressed for equitable access and treatment practices and to realize improved outcomes for all. Figure. Figure. Disclosures Ailawadhi: Amgen: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Pharmacyclics: Research Funding.

Abstract INTRODUCTION: Significant burden of pain syndromes are reported in patients with hematological malignancies undergoing HSCT mostly due to underlying disease and associated treatments. Opioid analgesics and benzodiazepines are routinely used for symptomatic management in this patient population. The use of narcotic analgesics and benzodiazepines in non-transplant hospitalized patients has been shown to adversely affect health related outcomes such as length-of-stay (LOS), falls and other complications. However, there is a significant knowledge gap regarding the patterns of opioid and benzodiazepine use and their impact on health outcomes in HSCT patients. METHODS: We identified 275 patients from the year 2015-2018 who underwent HSCT (allogeneic and autologous transplants) at our center for a variety of hematological malignancies. Opioid exposure was defined in three groups of patients 1) Opioid naïve: those did not report prior use of opioid at admission and who were not prescribed opioid during hospitalization, 2) Previous Opioid users: those who reported active use of opioid at admission and continued during hospitalization 3) New Opioid users: Patients who did not report opioid use at admission but were prescribed opioid during hospitalization. Multivariable analysis was performed to identify differences in opioid status, opioid use, benzodiazepine use, disease diagnosis, Karnofsky score, gender, age, race, and marital status with associated complications (Poisson regression), emergency department visits (Logistic Regression) and length of stay (Ordinal Logistic Regression) Figure 1 and Figure 2. RESULTS: The median age of patients was 59 (range: 25-74 ) years with slight male predominance (57%). Patients undergoing autologous transplants for multiple myeloma (MM) comprised 48% of the population. The majority (72 %) were exposed to opioid during hospitalization. Ninety two percent of the opioid naïve population (28% of the total population) underwent autologous transplant. Conversely, 36% of patients undergoing autologous transplants never received opiates during hospitalization as compared to 7% of those who received an allogeneic transplant. Median morphine milligram equivalent daily dose was 3.1 mg. Median diazepam equivalent daily dosage in patients that were opiate exposed was 2.07 milligram. Of the total transplant population, 55% received benzodiazepine concurrently with opiates during hospitalization. 76 % of the population was exposed to both opioid and benzodiazepine. Twenty five percent of those who were exposed to opioid did not receive benzodiazepines. Sixty four percent of the MM patients were exposed to opioid of which majority (59%) were previous opioid users. Of the non-MM patients undergoing HSCT, 80% were exposed to opioid of which 36% were previous opioid users and 64% were new users. A wide range of complications from neutropenic fever to death, were seen in 89% of all patients (opioid users and non-users) but all the falls occurred in patients who were on opioid medications. Autologous transplant recipients had higher odds of having a greater number of complications compared to Allogeneic transplant patients (OR 1.25, 95% CI: 1.01 - 1.55, p=0.04), as well as a reduced odds of having a medium or high length of stay (OR 0.03, 95% CI: 0.02 - 0.07). Of the opioid naïve patients, 6% presented to the ED within 30 days of discharge versus 15% of those that were exposed to opiates during hospitalization. Benzodiazepine use at admission for HSCT was associated with greater odd of presenting to ED within 30 days of discharge (OR 3.94, 95% CI: 1.55-10.04) and this was more significant in patients with MM (OR 4.08, 95% CI: 1.01-16.44). Finally, we also saw a trend towards longer stay in patients who were exposed to opioids as compared to opioid naïve (40% vs. 17%). CONCLUSION: Our study, albeit limited due to its retrospective design, is among the first to report the patterns of use and the impact of opioids and benzodiazepines in patients undergoing HSCT. Our results indicate that the use of these medications is frequent in this population and as in the non-transplant hospitalized patients and is associated with more emergency room visits post discharge, along with other potentially adverse outcomes. Disclosures Kharfan-Dabaja: Incyte Corp: Speakers Bureau; Seattle Genetics: Speakers Bureau; Alexion Pharmaceuticals: Speakers Bureau. Ailawadhi:Amgen: Consultancy; Pharmacyclics: Research Funding; Celgene: Consultancy; Takeda: Consultancy; Janssen: Consultancy.

Abstract Background: DLBCL is the most common adult NHL and despite significant advancements, outcomes in ethnic minorities remain suboptimal. Factors responsible for these disparities in ethnic minorities, especially variability in clinical and pathological features with evaluation of patient-level data have not been studied. Methods: A multi-institutional database of DLBCL patients seen at Mayo Clinic in Florida, University of Miami and University of Southern California between 1996-2016 was developed. Patient demographics, clinical disease characteristics and details of DLBCL immunophenotype [CD10, MUM1, BCL6 (Han's classification), Ki 67, MYC, BCL2) were reviewed. Comparisons between Hispanic and Non-Hispanic patients were made by Chi-square, Fischer's exact and Signed rank tests, where applicable. Patients with missing data on a certain feature were not included in the statistical analysis of that specific characteristic. Results: A total of 966 DLBCL patients with 69 Hispanics and 752 non-Hispanics were identified. These included 52% males (N=36) and 48% females (N=33) in Hispanics versus 58% males (N=436) and 42% females (N=316) in Non-Hispanics (p=0.35). Median age at diagnosis was significantly lower at 61 years (range 27-89) in Hispanics versus 66 in non-Hispanics (p=0.014). Extranodal disease was seen significantly more commonly in Hispanics (74%) than in non-Hispanics (60%) (p=0.037). There was no significant difference in disease stage at presentation between the two cohorts (p=0.189) although the proportion of patients with stage III and IV disease was higher among Hispanics (80.4%) as compared to non-Hispanics (68.5%). Similarly there was no significant difference in presence of primary CNS DLBCL at diagnosis between the two groups (p=0.74). GCB phenotype per the Hans' classification was seen in 59% (N=29) in both, Hispanics and Non-Hispanics (N=241) (p=0.99). Similarly, the median ki67 index of 80% was seen in both cohorts (p=0.48). MYC was positive in 59% in Hispanics versus only 37.5% in non-Hispanics (p=0.024). BCL2 expression by itself and also combined BCL2 and MYC double expression were not significantly different between the two groups (p=0.58 and p=0.11, respectively). Median overall survival (OS) was 22.5 months in Hispanics compared 54.9 months in Non-Hispanics (p<0.0001) (Figure 1). Conclusion: Survival outcome disparities in racial and ethnic minorities have been previously reported from population-based analyses. Lack of patient-level clinical data makes these analyses hypothesis generating, but not conclusive. We confirmed some prior findings including younger age at diagnosis for Hispanics with DLBCL. We also reported greater incidence of extranodal as well as stage III or IV disease at the time of presentation among Hispanics which may contribute to poor outcomes in this population. From DLBCL pathology standpoint, we found increased expression of MYC among Hispanics but no other significant immunohistochemical differences including double expression or non-GCB phenotype. The inferior OS despite uniform treatment practices at large Cancer Centers suggest multifactorial influences on patient outcomes which may at least in part include some of the differences we report here. Disclosures Ailawadhi: Pharmacyclics: Research Funding; Janssen: Consultancy; Takeda: Consultancy; Celgene: Consultancy; Amgen: Consultancy.

Abstract Background: Racial disparities in outcomes of cancer patients have been reported. Access to comprehensive cancer centers is associated with improved overall survival (OS) but racial/ethnic minorities may have a disparate access to such care. While the impact of treatment facility volume on outcomes has been evaluated, outcomes of centers with minority-predominant patient population have not been studied. We compared demographic profiles, facility level data and OS of patients treated at minority-predominant facilities to facilities that treated predominantly non-Hispanic Whites (NHW) with non-DLBCL. Methods: The National Cancer Database (NCDB) was used to identify all non-DLBCL patients diagnosed between 2004 and 2015. "Minority-treating facilities" were defined as facilities in the top decile by proportion for initial treatment of non-Hispanic African-Americans (NHAA), Hispanics and other races. We performed univariate and multivariate analyses to compare sociodemographic and clinical factors influencing outcomes between minority treating and non-minority treating facilities. A subgroup analysis stratified by race/ethnicity was also conducted to study the effect of treating facilities on the outcome of NHWs and minorities separately. Results: Of 1339 total facilities, 123 (9.1%) qualified as minority treating. Of 207,239 eligible patients in NCDB, 18,719 (9.03%) received treatment at the minority-treating facilities and of these, 11,190 (~60%) belonged to the minority races. Overall, 4.5% (6,988/156,664) NHWs and 30% (11,190/37,639) minorities received treatment at the minority-treating facilities. Several demographic and facility level characteristics were significantly different among the patients treated at minority-treating facilities as compared to non-minority treating facilities. Overall, significantly higher number of patients in minority-treating hospitals had lower income and education, had Medicaid coverage or lack of insurance. The OS of patients in minority treating facilities was significantly worse as compared to non-minority facilities (Figures). On multivariate analysis, patients who received treatment at minority-treating facilities were at 10% (HR=1.10, 95% CI: 1.06-1.14 p<0.001) higher risk of mortality as compared to those treated at the non-minority treating facilities. On multivariate analysis, NHAA (30% increased risk) and 'other races' (9% increased risk) were at significantly higher risk of mortality as compared to the NHW (Table 2). To study the effect of treatment at minority-treating facilities on OS among the patients of same race/ethnicity group, a multivariate analysis was also run separately for NHW and racial minorities. The NHWs who received treatment at minority-treating facilities were at 13% higher risk of death (HR=1.13, 95% CI: 1.08-1.19 p<0.001) as compared to NHWs who were treated at non-minority treating facilities. Similarly, the racial minorities who received treatment at minority treating facilities were at 8% higher risk of death (HR=1.08, 95% CI: 1.03-1.19 p=0.003) as compared to those who received treatment at the nonminority treating facilities. Conclusions:Outcomes of patients who received treatment at minority treating facilities was significantly worse than those at non-minority treating facilities. This was true for NHWs and racial minorities separately as well. Several demographic and facility level characteristics were significantly different in the two groups however OS remained worse after adjusting for them. Causes of poor outcomes at minority-treating facilities must be analyzed to mitigate them and improve outcomes for all. Figure. Figure. Disclosures Ailawadhi: Takeda: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Pharmacyclics: Research Funding.

Abstract Background: The treatment of NHL has witnessed a paradigm shift over time, with targeted immunotherapy, stem cell transplant (SCT) among others. Historically, XRT was used quite frequently for the management of NHL but with advent of better systemic therapy, its utilization has changed. Trends and patterns of care for XRT use have never been formally reported. Methods: We identified patients with NHL diagnosis in the National Cancer Database (NCDB) between years 2004 and 2015. Demographic, clinical, facility level, initial treatment and outcome data were collected. The utilization of XRT in diffuse large B-cell (DLBCL) and non-DLBCL NHL were analyzed separately by univariate and multivariate analyses. To analyze the trends in the rates of XRT, we applied segmented linear regression to calculate the average annual percent change (AAPC) and 95% confidence Interval (CI) with a 'p' value. AAPC and CIs were calculated using the segmented package in R studio v1.1.49. Rest of the analyses was conducted using StataCorp version 15.1. Results: A total of 133,182 DLBCL and 204,933 non-DLBCL patients were identified. Among patients with DLBCL, 27,895 (20.9%) patients received RT. The rate of XRT declined from 25% in 2004 to 18.4% in 2015 with estimated AAPC of -0.59% (95%CI: -0.70- -0.49), p= 0.03 (Figure 1). In a subgroup analysis, a similar decline in the rate of XRT was evident across all the age groups, combined stages I and II vs stages III and IV and nodal vs extra nodal DLBCL (Table 1). Among non DLBCL, 33,369 (16.3%) patients received XRT. There was a statistically significant decline in the rate of XRT from 18.03% in 2004 to 16.3% in 2014 with an AAPC of -0.26 (95%CI: -0.38- -0.14) p <0.001 (Figure 1). On the subgroup analysis, the utilization of XRT declined across all the studied subgroups except among patients aged 80 years and above (Table 1). On multivariate analysis, several demographic, clinical and facility level factors were found to be significantly associated with XRT utilization in NHL (Table 2). In particular, older age groups, racial/ethnic minorities, advanced stages, higher Charlson comorbidity scores and diagnosis in the more recent calendar years were associated with lesser chances of receiving RT. Extranodal DLBCL had lower utilization while extranodal non-DLBCL had increased XRT utilization. Conclusion: There has been a significant decline in the utilization of XRT among patients with NHL (DLBCL and non-DLBCL) in the US since 2004, likely due to introduction of practice changing systemic therapeutics. There is still significant heterogeneity noted in practice patterns regarding utilization of XRT across the US. Having more standardized guidelines will help streamline delivery of evidence-based patient care. Disclosures Ailawadhi: Celgene: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Takeda: Consultancy; Pharmacyclics: Research Funding.

Abstract Background: Clinical trials are fundamental to advance therapeutics systematically and improve patient outcomes. Despite this, enrollment on clinical trials remains dismal in the United States (US) and is a constant focus of healthcare policy. We studied distribution of clinical trials for B-cell malignancies over time across the US and unique clinical trial opportunities i.e. individual clinical trials for the given diagnosis at a site that patients may have access to participate. Methods: We abstracted data from clinicaltrials.gov for all trials that had non-Hodgkin lymphoma (NHL) or multiple myeloma (MM) as an inclusion indication between 1999-2018. Clinical trial characteristics and distribution over US geographical divisions (West, Midwest, Northeast, and South) were studied, and differences were assessed by Chi-square test. Results: A total of 1930 trials were identified (NHL: 982, MM: 948), of which 483 were recruiting at the time of data abstraction (NHL: 250, MM: 233). Over the past 2 decades, 182691 patients were enrolled on the various trials (NHL: 81592, MM: 101099). Trials by phase of study included phase 1: 629, phase 1/2: 316, phase 2: 813, phase 2/3: 11 and phase 3: 161. Number of trials by phase separated by NHL and MM are shown in Figure 1. Of these, 197 trials were randomized (NHL: 67, MM: 130). Geographical distribution of trials by diagnosis type is shown in Figure 2. A total of 31806 unique trial opportunities were noted for MM and NHL, of which 9,513 were international and 22,293 were in the US, with a geographical distribution of 5080 in West, 8198 in Midwest, 3944 in Northeast, and 5071 in South. 4,883 of the unique trial opportunities were available at NCI/NCCN accredited sites and 17,410 were at non-NCI/NCCN sites in the US. Treatment characteristics of the trials included monoclonal antibodies in 1218, other targeted agents in 2641, stem cell transplant in 526, and other agents in 517 trials with several trials utilizing more than one of these therapeutic options. There was no statistically significant difference in the distribution of clinical trials by phase of study across various US geographical regions for MM (p=0.71), NHL (p=0.98) or combined MM+NHL (p=0.16). On the other hand, unique trial opportunities were significantly different by study phase and geographical distribution for MM, NHL or MM+NHL (all p<0.001) (Figure 3). Conclusions: Widespread access to clinical trials within a cancer diagnosis is imperative for generalizability of trial results. In a comprehensive, national analysis we noted that while it may appear that clinical trials are available across the US, sites where they are open are distributed unevenly, giving rise to a disparity in access to evidence-based therapeutic advancements for patients. Disclosures Ailawadhi: Janssen: Consultancy; Amgen: Consultancy; Pharmacyclics: Research Funding; Takeda: Consultancy; Celgene: Consultancy. Sher:Affimed: Research Funding.

Abstract INTRODUCTION: Patients undergoing HSCT are reported to have a high prevalence of depression and anxiety. These comorbid mood disorders have been known to be associated with alteration in pain perception in patients without hematological malignancies. Pharmacological compounds such as opioid and benzodiazepines are frequently used to manage patient symptomology including pain and anxiety. Patients undergoing HSCT are a unique population where the impact of depression and anxiety on opioid and benzodiazepine use has not been well studied. METHODS: The study population consisted of patients who underwent HSCT at a single center for a variety of hematological malignancies from 2015-2018. Opioid and benzodiazepine exposure and dosage was defined in a) Patients who were exposed to opioid including those who were previously exposed and those who were exposed during hospitalization for HSCT b) Patients who were neither exposed to opioid previously, nor during the hospitalization for HSCT. Depression and Anxiety was defined as per PHQ-9 and GAD-7 scales prior to hospital admission. Multivariable analysis was performed to identify differences in opioid status, previous benzodiazepine use, transplant type, Karnofsky score, gender, age, race, and marital status with associated Diazepam Equivalent Daily Dosage (DEDD) (Negative Binomial Regression), and Morphine Milligram Equivalent Daily Dosages (MMEDD) (Logistic and Zero Truncated Negative Binomial Regression). RESULTS: A total of 275 patients underwent HSCT including autologous and allogeneic from 2015-2018. Anxious or depressed HSCT recipients had an increased incidence of higher DEDD with an IRR of 1.69 (95% CI: 1.15, 2.49) compared to those who were neither depressed nor anxious (Figure 1). However, patients who reported anxiety and depression did not have a different DEDD than those not anxious nor depressed. In addition, patients who were not naïve to benzodiazepine use prior to admission had an increased incidence of a higher DEDD [IRR of 2.23 (95% CI: 1.61, 3.05)]. Patients undergoing autologous stem cell transplant had a decreased incidence of receiving a higher DEDD [IRR of 0.65 (95% CI: 0.47-0.90)]. African American and other populations had a decreased incidence of receiving a higher DEDD [IRR of 0.40 (95% CI: 0.27, 0.59)]. Patients receiving higher MMEDD had a higher DEDD incidence [IRR of 1.01 (95% CI: 1.01, 1.02)]. Patients who were both anxious and depressed had increased odds of receiving an opioid [OR of 3.35 (95% CI: 1.62, 6.94)] compared to patients who were neither depressed nor anxious. However, patients who were either depressed or anxious did not have different odds of receiving an opioid compared to those who were neither depressed nor anxious. Patients undergoing autologous stem cell transplant had reduced odds of receiving an opioid [OR of 0.17 (95% CI: 0.07, 0.40)]. Patients with less than normal Karnofsky performance status (<90 on scale of 1-100) had an increased incidence of receiving a higher MMEDD [IRR of 2.34 (95% CI: 1.07, 5.12)] when modeled by Zero Truncated Negative Binomial Regression. Finally, HSCT recipients who were both anxious and depressed had reduced odds of being naïve to opioids [OR0.31 (95% CI: 0.15, 0.67)] compared to recipients who were neither depressed nor anxious. New opioid users had reduced odds of receiving a greater MMEDD [OR of 0.98 (95% CI: 0.96, 0.99)] when compared to previous users. In addition, autologous stem cell transplant recipients had reduced odds of receiving greater MMEDD compared to allogeneic transplant recipients (OR 0.33, 95% CI: 0.16, 0.66). CONCLUSION: Comorbid depression and /or anxiety impact opioid and benzodiazepine use in patients undergoing HSCT. The presence of these comorbid conditions and their association with increased use of opioids and benzodiazepines can also affect various health related outcomes. Larger studies are needed to fully understand the potential impact of this association on health related outcomes. Figure 1. Figure 1. Disclosures Kharfan-Dabaja: Incyte Corp: Speakers Bureau; Alexion Pharmaceuticals: Speakers Bureau; Seattle Genetics: Speakers Bureau. Ailawadhi:Amgen: Consultancy; Pharmacyclics: Research Funding; Celgene: Consultancy; Janssen: Consultancy; Takeda: Consultancy.

AbstractPurpose:CD38 has emerged as a high-impact therapeutic target in multiple myeloma, with the approval of daratumumab (anti-CD38 mAb). The clinical importance of CD38 in patients with chronic lymphocytic leukemia (CLL) has been known for over 2 decades, although it's relevance as a therapeutic target in CLL remains understudied.Experimental Design:We investigated the biological effects and antitumor mechanisms engaged by daratumumab in primary CLL cells. Besides its known immune-effector mechanisms (antibody-dependent cell-mediated cytotoxicity, complement-dependent death, and antibody-dependent cellular phagocytosis), we also measured direct apoptotic effects of daratumumab alone or in combination with ibrutinib. In vivo antileukemic activity was assessed in a partially humanized xenograft model. The influence of CD38 on B-cell receptor (BCR) signaling was measured via immunoblotting of Lyn, Syk, BTK, PLCγ2, ERK1/2, and AKT.Results:In addition to immune-effector mechanisms; daratumumab also induced direct apoptosis of primary CLL cells, which was partially dependent on FcγR cross-linking. For the first time, we demonstrated the influence of CD38 on BCR signaling where interference of CD38 downregulated Syk, BTK, PLCγ2, ERK1/2, and AKT; effects that were further enhanced by addition of ibrutinib. In comparison to single-agent treatment, the combination of ibrutinib and daratumumab resulted in significantly enhanced anti-CLL activity in vitro and significantly decreased tumor growth and prolonged survival in the in vivo CLL xenograft model.Conclusions:Overall, our data demonstrate the antitumor mechanisms of daratumumab in CLL; furthermore, we show how cotargeting BTK and CD38 lead to a robust anti-CLL effect, which has clinical implications.

Lysozyme amyloidosis (ALys) is an exceedingly rare autosomal dominant hereditary type of systemic amyloidosis that can be misdiagnosed as other common types of systemic amyloidosis. The gastrointestinal tract and the kidney are the most common sites of organ involvement. No specific treatment exists for ALys, and the management primarily consists of organ-directed supportive care. To our knowledge, this disorder has been previously reported only in European ancestries; here, we first report the occurrence of ALys in South Asian ancestry. This report highlights the need of awareness amongst physicians regarding the extension of this unique and challenging disorder to non-European ancestries.